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Genome-Wide Association Study and Admixture Mapping Reveal New Loci Associated with Total Ige Levels in Latinos

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Genome-Wide Association Study and Admixture Mapping Reveal New Loci Associated with Total Ige Levels in Latinos Henry Ford Health System Henry Ford Health System Scholarly Commons Center for Health Policy and Health Services Center for Health Policy and Health Services Research Articles Research 6-1-2015 Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos Maria Pino-Yanes Christopher R. Gignoux Joshua M. Galanter Albert M. Levin Henry Ford Health System, [email protected] Catarina D. Campbell See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/chphsr_articles Recommended Citation Pino-Yanes M, Gignoux CR, Galanter JM, Levin AM, Campbell CD, Eng C, Huntsman S, Nishimura KK, Gourraud P, Mohajeri K, O'Roak B, Hu D, Mathias RA, Nguyen EA, Roth LA, Padhukasahasram B, Moreno- Estrada A, Sandoval K, Winkler CA, Lurmann F, Davis A, Farber HJ, Meade K, Avila PC, Serebrisky D, Chapela R, Ford JG, Lenoir MA, Thyne SM, Brigino-Buenaventura E, Borrell LN, Rodriguez-Cintron W, Sen S, Kumar R, Rodriguez-Santana JR, Bustamante CD, Martinez FD, Raby BA, Weiss ST, Nicolae DL, Ober C, Meyers DA, Bleecker ER, Mack SJ, Hernandez RD, Eichler EE, Barnes KC, Williams KL, Torgerson DG, Burchard EG. Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos. Journal of Allergy and Clinical Immunology 2015; 135(6):1502-1510. This Article is brought to you for free and open access by the Center for Health Policy and Health Services Research at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Center for Health Policy and Health Services Research Articles by an authorized administrator of Henry Ford Health System Scholarly Commons. Authors Maria Pino-Yanes, Christopher R. Gignoux, Joshua M. Galanter, Albert M. Levin, Catarina D. Campbell, Celeste Eng, Scott Huntsman, Katherine K. Nishimura, Pierre-Antoine Gourraud, Kiana Mohajeri, Brian O'Roak, Donglei Hu, Rasika A. Mathias, Elizabeth A. Nguyen, Lindsey A. Roth, Badri Padhukasahasram, Andres Moreno-Estrada, Karla Sandoval, Cheryl A. Winkler, Fred Lurmann, Adam Davis, Harold J. Farber, Kelley Meade, Pedro C. Avila, Denise Serebrisky, Rocio Chapela, Jean G. Ford, Michael A. Lenoir, Shannon M. Thyne, Emerita Brigino-Buenaventura, Luisa N. Borrell, William Rodriguez-Cintron, Saunak Sen, Rajesh Kumar, Jose R. Rodriguez-Santana, Carlos D. Bustamante, Fernando D. Martinez, Benjamin A. Raby, Scott T. Weiss, Dan L. Nicolae, Carole Ober, Deborah A. Meyers, Eugene R. Bleecker, Steven J. Mack, Ryan D. Hernandez, Evan E. Eichler, Kathleen C. Barnes, Keoki L. Williams, Dara G. Torgerson, and Esteban G. Burchard This article is available at Henry Ford Health System Scholarly Commons: https://scholarlycommons.henryford.com/ chphsr_articles/135 Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos Maria Pino-Yanes, PhD,a,b Christopher R. Gignoux, PhD,a,c,d Joshua M. Galanter, MD, MAS,a,c Albert M. Levin, PhD,e Catarina D. Campbell, PhD,f Celeste Eng, BS,a Scott Huntsman, MS,a Katherine K. Nishimura, MHP,a Pierre-Antoine Gourraud, PhD,g Kiana Mohajeri, BS,f Brian J. O’Roak, PhD,f,h Donglei Hu, PhD,a Rasika A. Mathias, PhD,i Elizabeth A. Nguyen, BS,a Lindsey A. Roth, MA,a Badri Padhukasahasram, PhD,j Andres Moreno-Estrada, MD, PhD,d Karla Sandoval, MS, PhD,d Cheryl A. Winkler, PhD,k Fred Lurmann, MS,l Adam Davis, MA,m Harold J. Farber, MD, MSPH,n Kelley Meade, MD,m Pedro C. Avila, MD,o Denise Serebrisky, MD,p Rocio Chapela, MD,q Jean G. Ford, MD,r Michael A. Lenoir, MD,s Shannon M. Thyne, MD,t Emerita Brigino-Buenaventura, MD,u Luisa N. Borrell, DDS, PhD,v William Rodriguez-Cintron, MD,w Saunak Sen, PhD,x Rajesh Kumar, MD, MSPH,y Jose R. Rodriguez-Santana, MD,z Carlos D. Bustamante, MA, PhD,d Fernando D. Martinez, MD,aa,bb Benjamin A. Raby, MD, MPH,cc Scott T. Weiss, MD,cc Dan L. Nicolae, PhD,dd Carole Ober, PhD,dd Deborah A. Meyers, PhD,ee Eugene R. Bleecker, MD,ee Steven J. Mack, PhD,ff Ryan D. Hernandez, PhD,c Evan E. Eichler, PhD,f,gg Kathleen C. Barnes, PhD,i L. Keoki Williams, MD, PhD,j,hh Dara G. Torgerson, PhD,a and Esteban G. Burchard, MD, MPHa,c San Francisco, Palo Alto, Petaluma, Oakland, and Vallejo, Calif, Madrid, Spain, Detroit, Mich, Seattle, Wash, Portland, Ore, Baltimore and Frederick, Md, Houston, Tex, Chicago, Ill, Bronx, NY, Mexico City, Mexico, San Juan, Puerto Rico, Tucson, Ariz, Boston, Mass, and Winston-Salem, NC Background: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic Abbreviations used disorders. eQTL: Expression quantitative trait locus Objective: We sought to identify genetic variants associated GALA I: Genetics of Asthma in Latino Americans with IgE levels in Latinos. GALA II: Genes-environments & Admixture in Latino Americans GPHB5 Methods: We performed a genome-wide association study and : Glycoprotein hormone beta 5 GRAAD: Genetic Research on Asthma in the African Diaspora admixture mapping of total IgE levels in 3334 Latinos from the GWAS: Genome-wide association study Genes-environments & Admixture in Latino Americans (GALA II) Indel: Insertion-deletion study. Replication was evaluated in 454 Latinos, 1564 European KCNH5: Potassium voltage-gated channel, subfamily H Americans, and 3187 African Americans from independent studies. (eag-related), member 5 gene Results: We confirmed associations of 6 genes identified by means RHOJ: Ras homolog family member J gene of previous genome-wide association studies and identified a novel SNP: Single nucleotide polymorphism genome-wide significant association of a polymorphism in the zinc ZNF365: Zinc finger protein 365 gene finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P 5 2.3 3 1028). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P 5 4.95 3 1028). All but 22q13.1 IgE is a class of antibody involved in host defense mechanisms against parasitic infections.1,2 Increased total IgE levels are were replicated in an independent sample of Latinos, and 2 of the 1 3 peaks were replicated in African Americans (6p21.32-p22.1 and strongly associated with allergic disorders and asthma severity. Monoclonal antibodies against IgE have proved to be effective in 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide 4,5 significant single nucleotide polymorphisms in Latinos, 2 of which decreasing asthma exacerbations and allergic inflammation, replicated in European Americans. Another single nucleotide highlighting the importance of IgE in the cause of both asthma and allergic disease. polymorphism was peak-wide significant within 14q23.2 in 6-8 African Americans (rs1741099, P 5 3.7 3 1026) and replicated in The high heritability of IgE levels (47% to 80%), the clinical non–African American samples (P 5 .011). and biological relationship of IgE with atopic diseases, and the abil- ity to measure IgE levels in serum with a high precision make IgE a Conclusion: We confirmed genetic associations at 6 genes and 1,9 identified novel associations within ZNF365, HLA-DQA1, and useful endophenotype for the study of atopic diseases. Conse- quently, many linkage analyses and candidate gene association 14q23.2. Our results highlight the importance of studying 9 diverse multiethnic populations to uncover novel loci studies have identified genes associated with IgE levels. Recently, associated with total IgE levels. (J Allergy Clin Immunol 5 genome-wide association studies (GWASs) have revealed single 2015;135:1502-10.) nucleotide polymorphisms (SNPs) near 12 genes to be associated with IgE levels at a genome-wide significance level, including 6 Key words: IgE, genome-wide association study, admixture genes within the major MHC.10-13 mapping, allergy, asthma, next-generation sequencing, Latinos, Only 1% of subjects within prior GWASs were Latinos,10-14 Hispanics, minority populations and therefore studying diverse populations might uncover some 1502 Downloaded for Anonymous User (n/a) at Henry Ford Hospital / Henry Ford Health System (CS North America) from ClinicalKey.com by Elsevier on April 21, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved. J ALLERGY CLIN IMMUNOL PINO-YANES ET AL 1503 VOLUME 135, NUMBER 6 of the additional missing heritability of IgE levels.15 This is levels, as shown for other traits and diseases.22-24 Therefore in particularly relevant for studies of IgE because it is known to this study we reasoned that novel genetic variants associated vary by race-ethnicity in the United States, with higher levels with IgE levels in Latinos could be identified through a reported in both Latinos and African Americans compared with combination of GWAS and admixture mapping. European Americans.16-19 Differences in IgE levels among ethnic groups might in part be due to variation in the frequencies of risk alleles for high IgE levels resulting from different proportions of METHODS Native American, European, and African genetic ancestry at an Study populations individual locus (local ancestry). Consistent with this, African Genes-environments & Admixture in Latino ancestry has been associated with higher IgE levels in populations 20,21 Americans (GALA II) study. A total of 3334 participants were of African descent, suggesting that admixture mapping could used for discovery (see Table E1 in this article’s Online Repository at be a powerful tool to identify novel loci associated with IgE www.jacionline.org). The GALA II study is an ongoing, multicenter From the Departments of aMedicine, cBioengineering and Therapeutic Sciences, and Affymetrix.
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